How the brain develops from a proliferating progenitor pool into the most intricate structure in the human body is a fundamental question in modern biology. The work proposed here investigates this question in the telencephalon, the embryonic structure that gives rise to the cerebral cortex and other areas of higher brain function. Specifically, these studies will explore the role of NF-kB signaling during telencephalic development. The NF-kB pathway has been intensively studied primarily in the context of the immune system where it plays a central role during development and in the adult. While some studies suggest a role for NF-kB in mature neurons, currently almost nothing is known about the role of this pathway in the embryonic forebrain. However, recent evidence suggests that this pathway is activated throughout telencephalic development and thus is likely to influence that process. This activation is particularly strong in the proliferative zone, supporting a role for NF-kB signaling in that region. Therefore, we will examine the effects of activating or blocking NF-kB in telencephalic progenitors on cell survival, proliferation, and fate both in vivo and in vitro. In particular we will use viral vectors for gene delivery, ultrasound-guided in utero surgery for in vivo studies, and both attached and neurosphere cultures for in vitro studies. These efforts will test the hypothesis that the predominant role of NF-kB signaling in the telencephalic proliferative zone is to promote the survival and maintenance of the progenitor pool. The studies will also consider potential interactions between the NF-kB, Notch, and FGF signaling pathways during telencephalic development. Numerous studies have suggested that these pathways can interact in the immune system and elsewhere, although the exact nature of those interactions remains unclear. Based upon the exploratory nature of this work we are requesting R21 level funding. The identification of NF-kB as relevant for mammalian forebrain development would be an important step in understanding this fundamental process. [unreadable] [unreadable] [unreadable]